Immune profiling reveals umbilical cord blood mononuclear cells from South India display an IL-8 dominant, CXCL-10 deficient polyfunctional monocyte response to pathogen-associated molecular patterns (PAMPs) that is distinct from adult blood cells.

Neonate responses to pathogen-associated molecular patterns (PAMPS) differ from adults; such understanding is poor in Indian neonates, despite recognised significant infectious risk. Immune profiling analysis was undertaken of ten secreted mediators contextualised with cellular source induced by six PAMPs in umbilical cord (CB; n=21) and adult-blood (PBMC, n=14) from a tertiary care hospital in South India. Differential cytokine expression analysis (minimum log2-fold difference; adj p-value<0.05) identified bacterial PAMPs induced higher concentrations of IL-1ß, IL-10, TNF-α in adults versus IL-8, GM-CSF, IFN-γ and IL-2 in CB. CB responded to poly I:C and SARS-CoV-2 lysate with a dominant IL-8 response, whereas, in PBMC, CXCL-10 dominated poly I:C, but not SARS-CoV-2, responses, highlighting potential IL-8 importance, in absence of Type I Interferons, in antiviral CB immunity. Candida albicans was the only PAMP to uniformly induce higher secretion of effectors in CB. The predominant source of IL-8/IL-6/TNF-α/IL-1ß in both CB and PBMC was polyfunctional monocytes and IFN-γ /IL-2/IL-17 from innate lymphocytes. Correlation matrix analyses revealed IL-8 to be the most differentially regulated, correlating positively in CB versus negatively in PBMC with IL-6, GM-CSF, IFN-γ, IL-2, consistent with more negatively regulated cytokine modules in adults, potentially linked to higher anti-inflammatory IL-10. Cord and adult blood from India respond robustly to PAMPs with unique effector combinations. These data provide a strong foundation to monitor, explore, mechanisms that regulate such immunity during the life course, an area of significant global health importance given infection-related infant mortality incidence.

Tumour immunogenicity goes with the (mitochondrial electron) flow.

Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T-cell-mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC-APP genes or dampened interferon signalling.

GRADE-ADOLOPMENT of hyperthyroidism treatment guidelines for a Pakistani context.

INTRODUCTION: The prevalence of hyperthyroidism in Pakistan is 2.9%, which is two times higher than in the United States. Most high-quality hyperthyroidism clinical practice guidelines (CPGs) used internationally originate from high-income countries in the West. Local CPGs in Pakistan are not backed by transparent methodologies. We aimed to produce comprehensive, high-quality CPGs for the management of hyperthyroidism in Pakistan. METHODS: We employed the GRADE-ADOLOPMENT approach utilizing the 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis as the source CPG. Recommendations from the source guideline were either adopted as is, excluded, or adapted according to our local context. RESULTS: The source guideline included a total of 124 recommendations, out of which 71 were adopted and 49 were excluded. 4 recommendations were carried forward for adaptation via the ETD process, with modifications being made to 2 of these. The first addressed the need for liver function tests (LFTs) amongst patients experiencing symptoms of hepatotoxicity while being treated with anti-thyroid drugs (ATDs). The second pertained to thyroid status testing post-treatment by radioactive iodine (RAI) therapy for Graves' Disease (GD). Both adaptations centered around the judicious use of laboratory investigations to reduce costs of hyperthyroidism management. CONCLUSION: Our newly developed hyperthyroidism CPGs for Pakistan contain two context-specific modifications that prioritize patients' finances during the course of hyperthyroidism management and to limit the overuse of laboratory testing in a resource-constrained setting. Future research must investigate the cost-effectiveness and risk-benefit ratio of these modified recommendations.

Immunogenicity of SARS-CoV-2 vaccines BBV152 (COVAXIN®) and ChAdOx1 nCoV-19 (COVISHIELD™) in seronegative and seropositive individuals in India: a multicentre, nonrandomised observational study.

Background: There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the age group 18-45 years began in April 2021 when seropositivity rates in the general population were rising due to the delta wave of COVID-19 pandemic during April-May 2021. Methods: Between June 30, 2021, and Jan 28, 2022, we enrolled 691 participants in the age group 18-45 years across four clinical sites in India. In this non-randomised and laboratory blinded study, participants received either two doses of Covaxin® (4 weeks apart) or two doses of Covishield™ (12 weeks apart) as per the national vaccination policy. The primary outcome was the seroconversion rate and the geometric mean titre (GMT) of antibodies against the SARS-CoV-2 spike and nucleocapsid proteins post two doses. The secondary outcome was the frequency of cellular immune responses pre- and post-vaccination. Findings: When compared to pre-vaccination baseline, both vaccines elicited statistically significant seroconversion and binding antibody levels in both seronegative and seropositive individuals. In the per-protocol cohort, Covishield™ elicited higher antibody responses than Covaxin® as measured by seroconversion rate (98.3% vs 74.4%, p < 0.0001 in seronegative individuals; 91.7% vs 66.9%, p < 0.0001 in seropositive individuals) as well as by anti-spike antibody levels against the ancestral strain (GMT 1272.1 vs 75.4 binding antibody units/ml [BAU/ml], p < 0.0001 in seronegative individuals; 2089.07 vs 585.7 BAU/ml, p < 0.0001 in seropositive individuals). As participants at all clinical sites were not recruited at the same time, site-specific immunogenicity was impacted by the timing of vaccination relative to the delta and omicron waves. Surrogate neutralising antibody responses against variants-of-concern including delta and omicron was higher in Covishield™ recipients than in Covaxin® recipients; and in seropositive than in seronegative individuals after both vaccination and asymptomatic infection (omicron variant). T cell responses are reported from only one of the four site cohorts where the vaccination schedule preceded the omicron wave. In seronegative individuals, Covishield™ elicited both CD4+ and CD8+ spike-specific cytokine-producing T cells whereas Covaxin® elicited mainly CD4+ spike-specific T cells. Neither vaccine showed significant post-vaccination expansion of spike-specific T cells in seropositive individuals. Interpretation: Covishield™ elicited immune responses of higher magnitude and breadth than Covaxin® in both seronegative individuals and seropositive individuals, across cohorts representing the pre-vaccination immune history of most of the vaccinated Indian population. Funding: Corporate social responsibility (CSR) funding from Hindustan Unilever Limited (HUL) and Unilever India Pvt. Ltd. (UIPL).

ACTION APAC: Understanding perceptions, attitudes and behaviours in obesity and its management across south and Southeast Asia.

To identify perceptions and attitudes among people with obesity (PwO) and healthcare professionals (HCPs) toward obesity and its management in nine Asia-Pacific (APAC) countries, a cross-sectional online survey was conducted among adult PwO with self-reported body mass index of ≥25 kg/m2 (≥27 kg/m2, Singapore), and HCPs involved in direct patient care. In total, 10 429 PwO and 1901 HCPs completed the survey. Most PwO (68%) and HCPs (84%) agreed that obesity is a disease; however, a significant proportion of PwO (63%) and HCPs (41%) believed weight loss was the complete responsibility of PwO and only 43% of PwO discussed weight with an HCP in the prior 5 years. Most respondents acknowledged that weight loss would be extremely beneficial to PwO's overall health (PwO 76%, HCPs 85%), although nearly half (45%) of PwO misperceived themselves as overweight or of normal weight. Obesity was perceived by PwO (58%) and HCPs (53%) to negatively impact PwO forming romantic relationships. HCPs cited PwOs' lack of interest (41%) and poor motivation (37%) to lose weight as top reasons for not discussing weight. Most PwO (65%) preferred lifestyle changes over medications to lose weight. PwO and HCPs agreed that lack of exercise and unhealthy eating habits were the major barriers to weight loss. Our data highlights a discordance between the understanding of obesity as a disease and the actual behaviour and preferred approaches to manage it among PwO and HCPs. The study addresses a need to align these gaps to deliver optimal care for PwO.

BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.

Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against non-tuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.

Variations in Site-Specific Costs for Infants Born Extremely Preterm in Canadian Neonatal Intensive Care Units.

OBJECTIVE: To quantify site-specific costs and their association with survival without major morbidity (SWMM) in Canada for neonates <28 weeks of gestation admitted to large tertiary neonatal intensive care units. METHODS: We conducted a retrospective analysis of infants born at <28 weeks of gestation and admitted to Canadian Neonatal Network sites from 2010 through 2021. Sites that cared for at least 50 eligible infants by gestational age in weeks over the study period were included. Using a validated costing algorithm that assessed physician, nursing, respiratory therapy, diagnostic imaging, transfusions, procedural, medication, and certain indirect costs, we calculated site and resource-specific costs in 2017 Canadian dollars (CAD) and evaluated their relationship with SWMM. RESULTS: Seven sites with 8180 (range 841-1605) eligible neonates with a mean (SD) gestation of 25.4 [1.3] weeks were included. Survival to discharge or transfer was 85.3% with a mean (SD) length of stay of 75 (46) days. The mean (SD) total and daily costs per neonate varied between $94 992 ($60 283) and $174 438 ($130 501) CAD and $1833 ($916) to $2307 ($1281) CAD, respectively. Between sites, there was no relationship between costs and SWMM. CONCLUSIONS: There was marked variation in costs and SWMM between sites in Canada with universal health care. The lack of concordance between both outcomes and costs among sites may provide possibilities for outcomes improvement and cost containment.

Reference Interval of Soluble FMS­like Tyrosine Kinase­1 in Non-Pregnant and Pregnant Females: A Novel Biomarker for Pre-eclampsia.

OBJECTIVE: To determine the reference interval of soluble FMS-like tyrosine kinase-1 (sFIt-1) in healthy, non-pregnant and pregnant females. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Chemical Pathology, Chughtai Institute of Pathology, Lahore, from January to May 2023. METHODOLOGY: Blood samples were collected from 120 disease-free non-pregnant females of reproductive age group and 120 disease-free pregnant females with singleton fetuses from 15 to 28 weeks of gestational age. Healthy reference individuals were selected by correlating history with medical disorders like diabetes mellitus, hypertension, autoimmune diseases, inherited disorders, and by excluding any other drug history. All findings were recorded on health screening questionnaire. Levels of sFlt-1 were measured by a fully automated immunoassay analyser Cobas e601. Kolmogorov-Smirnov test was applied. The value of p <0.05 was considered significant. The 2.5th and 97.5th percentiles were computed at 90% CI by using the formula 0.025x (n+1) and 0.975x (n+1) which corresponded to rank number 1 and 7, respectively. The reference interval was calculated by the Rank-based method. RESULTS: Reference interval of sFlt-1 in non-pregnant and pregnant females were determined on the basis of 2.5th and 97.5th percentiles which were 57.7 to 118.5 pg/mL and 563.5 to 3288.0 pg/mL, respectively. CONCLUSION: The present study determined reference interval of sFlt-1 in healthy, non-pregnant and pregnant females in Lahore. KEY WORDS: Reference interval, Soluble FMS-like tyrosine kinase-1, Pre-eclampsia, Rank-based method.

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways.

This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6 in HLA-DR+CD16-CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16-CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1ß, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Polyfunctional CD4 T-cells correlating with neutralising antibody is a hallmark of COVISHIELDTM and COVAXIN® induced immunity in COVID-19 exposed Indians.

Detailed characterisation of immune responses induced by COVID-19 vaccines rolled out in India: COVISHIELDTM (CS) and COVAXIN® (CO) in a pre-exposed population is only recently being discovered. We addressed this issue in subjects who received their primary series of vaccination between November 2021 and January 2022. Both vaccines are capable of strongly boosting Wuhan Spike-specific neutralising antibody, polyfunctional Th1 cytokine producing CD4+ T-cells and single IFN-γ + CD8+ T-cells. Consistent with inherent differences in vaccine platform, the vector-based CS vaccine-induced immunity was of greater magnitude, breadth, targeting Delta and Omicron variants compared to the whole-virion inactivated vaccine CO, with CS vaccinees showing persistent CD8+ T-cells responses until 3 months post primary vaccination. This study provides detailed evidence on the magnitude and quality of CS and CO vaccine induced responses in subjects with pre-existing SARS-CoV-2 immunity in India, thereby mitigating vaccine hesitancy arguments in such a population, which remains a global health challenge.

Factors associated with Diabetes Empowerment among patients with type 2 diabetes, at OPD setting, Karachi, Pakistan.

Diabetes Empowerment is important for diabetic control as it postpones the onset of complications. This study aimed to investigate the association of medication adherence, self-care behaviors, and diabetes knowledge with Diabetes Empowerment among patients with type II diabetes. A cross-sectional study was conducted on 451 type II diabetes patients attending Endocrinology clinics at OPD setting in Karachi. Data was collected electronically using a structured questionnaire comprising of tools to measure Diabetes Empowerment, medication adherence, self-care behaviors, diabetes knowledge, and socioeconomic scale. It also included health-related information from patients' medical record. As outcome variable was continuous, so multiple linear regression analysis was used to assess the independent effect of Diabetes Empowerment on medication adherence, self-care behaviors and diabetes knowledge with other co-variates. The mean Diabetes Empowerment score was 3.62 (SD = 0.31). The mean age of the participants was 56.68 (SD = 11.76). 53.88% were females, 80.71% were married, 77.56% were obese, and 66.30% were upper-middle class with average diabetes duration of 11.7 years (SD = 7.89). HbA1c values were ≥ 7 in 63.41% of study participants. Diabetes Empowerment was significantly associated with medication adherence (P = 0.001), general diet (P < 0.001), special diet (P = 0.011), smoking status (P = 0.001), and socioeconomic status (upper lower, P = 0.085). A comprehensive strategy for the treatment of type II diabetes is essential to enhance clinical results, improve patient quality of life, and prevent diabetes-related comorbidities. People with type II diabetes should be encouraged to embrace an empowerment-based approach by healthcare providers. It is critical to do research that promotes empowerment.

Immune escape of colorectal tumours via local LRH-1/Cyp11b1-mediated synthesis of immunosuppressive glucocorticoids.

Control of tumour development and growth by the immune system critically defines patient fate and survival. What regulates the escape of colorectal tumours from destruction by the immune system remains currently unclear. Here, we investigated the role of intestinal synthesis of glucocorticoids in the tumour development during an inflammation-induced mouse model of colorectal cancer. We demonstrate that the local synthesis of immunoregulatory glucocorticoids has dual roles in the regulation of intestinal inflammation and tumour development. In the inflammation phase, LRH-1/Nr5A2-regulated and Cyp11b1-mediated intestinal glucocorticoid synthesis prevents tumour development and growth. In established tumours, however, tumour-autonomous Cyp11b1-mediated glucocorticoid synthesis suppresses anti-tumour immune responses and promotes immune escape. Transplantation of glucocorticoid synthesis-proficient colorectal tumour organoids into immunocompetent recipient mice resulted in rapid tumour growth, whereas transplantation of Cyp11b1-deleted and glucocorticoid synthesis-deficient tumour organoids was characterized by reduced tumour growth and increased immune cell infiltration. In human colorectal tumours, high expression of steroidogenic enzymes correlated with the expression of other immune checkpoints and suppressive cytokines, and negatively correlated with overall patients' survival. Thus, LRH-1-regulated tumour-specific glucocorticoid synthesis contributes to tumour immune escape and represents a novel potential therapeutic target.

In utero Exposure to Maternal Diabetes and the Risk of Cerebral Palsy: A Population-based Cohort Study.

BACKGROUND: Evidence on the effects of in utero exposure to maternal diabetes on cerebral palsy (CP) in offspring is limited. We aimed to examine the effects of pregestational (PGDM) and gestational diabetes (GDM) separately on CP risk and the mediating role of increased fetal size. METHODS: In a population-based study, we included all live births in Ontario, Canada, between 2002 and 2017 followed up through 2018 (n = 2,110,177). Using administrative health data, we estimated crude and adjusted associations between PGDM or GDM and CP using Cox proportional hazards models to account for unequal follow-up in children. For the mediation analysis, we used marginal structural models to estimate the controlled direct effect of PGDM (and GDM) on the risk of CP not mediated by large-for-gestational age (LGA). RESULTS: During the study period, 5,317 children were diagnosed with CP (187 exposed to PGDM and 171 exposed to GDM). Children of mothers with PGDM showed an increased risk (hazard ratio [HR]: 1.84 [95% confidence interval (CI): 1.59, 2.14]) after adjusting for maternal sociodemographic and clinical factors. We found no associations between GDM and CP (adjusted HR: 0.91 [0.77, 1.06]). Our mediation analysis estimated that LGA explained 14% of the PDGM-CP association. CONCLUSIONS: In this population-based birth cohort study, maternal pregestational diabetes was associated with increased risk of CP, and the increased risk was not substantially mediated by the increased fetal size.

Differences in Immune Responses in Individuals of Indian and European Origin: Relevance for the COVID-19 Pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic, large differences in susceptibility and mortality due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported between populations in Europe and South Asia. While both host and environmental factors (including Mycobacterium bovis BCG vaccination) have been proposed to explain this, the potential biological substrate of these differences is unknown. We purified peripheral blood mononuclear cells from individuals living in India and the Netherlands at baseline and 10 to 12 weeks after BCG vaccination. We compared chromatin accessibility between the two populations at baseline, as well as gene transcription profiles and cytokine production capacities upon stimulation. The chromatin accessibility of genes important for adaptive immunity was higher in the Indians than in the Europeans, while the latter had more accessible chromatin regions in genes of the innate immune system. At the transcriptional level, we observed that the Indian volunteers displayed a more tolerant immune response to stimulation, in contrast to a more exaggerated response in the Europeans. BCG vaccination strengthened the tolerance program in the Indians but not in the Europeans. These differences may partly explain the different impact of COVID-19 on the two populations. IMPORTANCE In this study, we assessed the differences in immune responses in individuals from India and Europe. This aspect is of great relevance, because of the described differences in morbidity and mortality between India and Europe during the pandemic. We found a significant difference in chromatin accessibility in immune cells from the two populations, followed by a more balanced and effective response in individuals from India. These exciting findings represent a very important piece of the puzzle for understanding the COVID-19 pandemic at a global level.

Alteration of the central core of a DF-PCIC chromophore to boost the photovoltaic applications of non-fullerene acceptor based organic solar cells.

Modifying the central core is a very efficient strategy to boost the performance of non-fullerene acceptors. Herein five non-fullerene acceptors (M1-M5) of A-D-D'-D-A type were designed by substituting the central acceptor core of the reference (A-D-A'-D-A type) with different strongly conjugated and electron donating cores (D') to enhance the photovoltaic attributes of OSCs. All the newly designed molecules were analyzed through quantum mechanical simulations to compute their optoelectronic, geometrical, and photovoltaic parameters and compare them to the reference. Theoretical simulations of all the structures were carried out through different functionals with a carefully selected 6-31G(d,p) basis set. Absorption spectra, charge mobility, dynamics of excitons, distribution pattern of electron density, reorganization energies, transition density matrices, natural transition orbitals and frontier molecular orbitals, respectively of the studied molecules were evaluated at this functional. Among the designed structures in various functionals, M5 showed the most improved optoelectronic properties, such as the lowest band gap (2.18 e V), highest maximum absorption (720 nm), and lowest binding energy (0.46 eV) in chloroform solvent. Although the highest photovoltaic aptitude as acceptors at the interface was perceived to be of M1, its highest band gap and lowest absorption maxima lowered its candidature as the best molecule. Thus, M5 with its lowest electron reorganization energy, highest light harvesting efficiency, and promising open-circuit voltage (better than the reference), amongst other favorable features, outperformed the others. Conclusively, each evaluated property commends the aptness of designed structures to augment the power conversion efficiency (PCE) in the field of optoelectronics in one way or another, which reveals that a central un-fused core having an electron-donating capability with terminal groups being significantly electron withdrawing, is an effective configuration for the attainment of promising optoelectronic parameters, and thus the proposed molecules could be utilized in future NFAs.

Novel A-π-D-π-A type non-fullerene acceptors of dithienyl diketopyrropopyrrole derivatives to enhance organic photovoltaic applications: a DFT study.

To boost the photovoltaic attributes of organic photovoltaic cells, seven dithienyl diketopyrropopyrrole (TDPP) donor-based A-π-D-π-A (acceptor-bridge-donor-bridge-acceptor) type molecules (TM1-TM7) were formulated by modifying the electron accepting ends of the reference molecule (TMR). Optical and quantum chemical parameters of seven synthesized molecules were investigated using density functional theory with the MPW1PW91/6-31G(d,p) functional. Several parameters that can be used to measure and improve the efficiency of solar cells have been analyzed and summed up. These parameters include binding energy of exciton, excitation energy of electron, reorganization energies, dipole moment, molecular electrostatic potential, charge mobility, wavelength of maximum absorption, open circuit voltage, short circuit current, fill factor, density of states, transition density matrices, as well as iso-surface and non-covalent interactions. Thus, all of our proposed structures are perceived to be superior to the reference in terms of the maximum possible solar energy yield in solar cells with bulk heterojunctions, as determined by analyses of our designed molecules for the aforementioned parameters.

In Utero Exposure to Maternal Injury and the Associated Risk of Cerebral Palsy.

Importance: Although maternal unintentional injury during pregnancy has shown negative impacts on the mother and fetus, the evidence on its long-term associations with children's neurodevelopment is limited. Objective: To examine the association between maternal unintentional injury and cerebral palsy (CP) in offspring. Design, Setting, and Participants: This was a population-based, longitudinal, cohort study of all in-hospital live births born between April 1, 2002, and March 31, 2017, in a publicly funded health care system setting of Ontario, Canada. Infants born more than 20 weeks' gestation were included and followed up until March 31, 2018. Excluded from the analysis were stillbirths, infants with missing or invalid records, and births with missing or invalid birth characteristics. Data were analyzed from March 1 to June 30, 2021. Exposures: Maternal unintentional injury during pregnancy ascertained based on inpatient or emergency department diagnoses. Main Outcomes and Measures: CP diagnosis between birth and the end of follow-up in 2018 with the CP case definition of a single inpatient or 2 or more outpatient diagnoses at least 2 weeks apart between birth and age 16 years. Results: Of 2 110 177 children included in this study (mean [SD] gestational age, 38.8 [1.9] weeks; 1 082 520 male [51.3%]), 81 281 (3.9%) were exposed in utero to maternal unintentional injury. During a median (IQR) follow-up time of 8 (4-12) years, 5317 children (0.3%) were diagnosed with CP (292 CP cases [5.5%] were exposed to maternal unintentional injury). The mean incidence rates of CP were 4.36 and 2.93 per 10 000 child-years in the exposed and the unexposed group, respectively. Children exposed to maternal unintentional injury had a modest increase in the risk of CP, compared with those unexposed (hazard ratio [HR], 1.33; 95% CI, 1.18-1.50) after adjusting for maternal sociodemographic and clinical characteristics. Severe injuries that resulted in hospitalization and delivery within 1 week from the injury conferred higher risks of CP (adjusted HR, 2.18; 95% CI, 1.29-3.68 and adjusted HR, 3.40; 95% CI, 1.93-6.00, respectively). Results were robust in multiple bias analyses. Conclusions and Relevance: In this Canadian population-based birth cohort study, in utero exposure to maternal unintentional injury was associated with an increased risk of CP, with a higher risk with more severe injuries. These findings fill an important gap in knowledge on the potential role of maternal injury on children's neurodevelopment outcomes. Public health professionals and stakeholders should be aware of these potential long-term consequences on offspring when designing programs and providing recommendations about safety during pregnancy. Early monitoring and developmental assessment of children exposed to maternal injury might be warranted.

Optimizing Ramadan fasting: A randomised controlled trial for people with type 2 diabetes during Ramadan applying the principles of the ADA/EASD consensus.

BACKGROUND: Fasting during the holy month of Ramadan is one of the five pillars of Islam. Fasting is not meant to create excessive hardship on the Muslim individual according to religious tenets. It is important that health professionals are aware of potential risks associated with fasting during the month of Ramadan (mainly hypoglycemia and hyperglycemia). AIMS: To explore the impact of applying the principles of our 2020 recommendations for the management of type 2 diabetes (T2D) during the month of Ramadan. METHODS: A multinational randomized controlled trial (RCT) was conducted in five Muslim majority countries. Six hundred and sixty participants were deemed eligible for the study; however, 23% declined to participate later for various reasons. In total, 506 participants were enroled and were equally randomized to the intervention or the control group. At the end of the study, data from 231 participants in the intervention group and 221 participants from the control group were collected after 12.6% and 8.7% were, respectively, lost to follow-up. Participants were randomized to receive a Ramadan-focussed education with treatment for diabetes adjusted as per our 2020 recommendation update compared with the local usual care (control group). Results are presented using mean, standard deviation, odds ratio (OR), and percentages. RESULTS: At the end of the study, the number of hypoglycemic episodes in the intervention group was less than in participants who received usual care. The intervention group had significantly lower severe hypoglycemia compared to the control group with an OR of 0.2 [0.1-0.8]. Compared to baseline, both groups had a significant reduction in glycated haemoglobin (HbA1c), but the improvements were significantly greater in the intervention group. Whilst body weight reduced and high-density lipoprotein cholesterol increased with the intervention, these changes were not significantly different from usual care. CONCLUSIONS: A pre-Ramadan assessment of people with T2D coupled with pre-Ramadan education and an adjustment of glucose-lowering treatment as per our updated 2020 recommendations can prevent acute complications and allow a safer fast for people with T2D. We have shown that such an approach reduces the risk of developing severe hypoglycemia and improves the metabolic outcomes in people with T2D.

Prevalence and temporal trends of cerebral palsy in children born from 2002 to 2017 in Ontario, Canada: Population-based cohort study.

AIM: To examine the prevalence and temporal trends of cerebral palsy (CP) overall and by population characteristics. METHOD: We identified 2 110 177 live births born in the province of Ontario, Canada, between 2002 and 2017 using administrative health data and estimated CP prevalence in children aged 0 to 16 years overall and by specific population characteristics. We also examined temporal trends in CP rates - overall and by characteristics - in young children (0-4 years) by their year of birth between 2002 and 2013 (n=1 587 087 live births) to allow for an equal follow-up time (4 years and 364 days) for all children. RESULTS: Overall CP prevalence among children aged 0 to 16 years was 2.52 (95% confidence interval 2.45-2.59) per 1000 live births. CP rates in ages 0 to 4 years peaked at 2.86 in 2007 births, but steadily declined afterwards to 1.94 per 1000 live births in 2013. CP rates were higher in children born preterm, small for gestational age, males, multiples, children with congenital malformations, and in children of young (<20 years), old (≥40 years), primiparous, or grand multiparous (≥4) mothers; differences by these characteristics decreased over time. We observed socioeconomic disparities in CP rates that persisted over time. INTERPRETATION: Despite the decreasing trend of CP rates overall, CP rates varied by the child and maternal characteristics over time. WHAT THIS PAPER ADDS: Overall cerebral palsy (CP) prevalence was 2.5 per 1000 live births among children born from 2002 to 2017. CP prevalence peaked in children born in 2007 then steadily decreased between 2007 and 2013. Changes in CP rates varied over time by child and maternal characteristics. Socioeconomic inequalities in CP persisted and remained stable over the study period.